Mutation of p53, inherited in some individuals with Li-Fraumeni Syndrome (LFS), is a critical event in the elaboration of many tumors of diverse origin. Recent data, however, suggest that other genetic alterations also result in the cancer predisposition typical for LFS. The mapping of this locus should yield insight into other genetic events that lead to the genesis of diverse tumor. In addition, since 82% of LFS patients inheriting mutations of p53 inherit a missense mutation in p53, we have created a mouse model containing an arg to his substitution at amino acid 172 of the endogenous p53 gene. This mutation corresponds to the hot spot mutation at amino acid 175 altered in 6% of human tumors. Comparison of p53 missense and null alleles in the mouse will yield valuable insight into the in vivo differences between p53 mutants. Additional genetic events that may modify the ability of p53 to function are suggested by experiments using another mouse model (CE/J) in which heterozygosity or homozygosity at the p53 locus results in embryo lethality. This modifier of p53, mop 1, will also be mappe4d in this study.